RNA Pol-II dependent transcription efficiency fine-tunes A-to-I editing levels

A-to-I RNA-editing is a widespread epitranscriptomic phenomenon leading to the conversion of adenosines to inosines, which are primarily interpreted as guanosines by cellular machines. Consequently, A-to-I editing can alter splicing or lead to re-coding of transcripts. As misregulation of editing can cause a variety of human diseases, A-to-I editing requires tight regulation of the extent of deamination, particularly in protein-coding regions. The bulk of A-to-I editing occurs co-transcriptionally. Thus, we studied A-to-I editing regulation in the context of transcription and pre-mRNA processing. We show that stimulation of transcription impacts editing levels. Activation of the transcription factor MYC leads to an upregulation of A-to-I editing, particularly in transcripts that are suppressed upon MYC activation. Moreover, low pre-mRNA synthesis rates and low pre-mRNA expression levels support high levels of editing. We also show that editing levels greatly differ between nascent pre-mRNA and mRNA in a cellular system as well as in mouse tissues. Editing levels can increase or decrease from pre- to mRNA and vary across editing targets and across tissues showing that pre-mRNA processing is an important layer of editing-regulation. Several lines of evidence suggest that the differences emerge during pre-mRNA splicing. Moreover, Actinomycin D treatment of primary neuronal cells and editing level analysis suggests that regulation of editing levels also depends on transcription.